Clinical evaluation of new diagnostic modalities of EUS for pancreatobiliary diseases

Transcription

1 Digestive Endoscopy 2015; 27 (Suppl. 1): doi: /den Clinical evaluation of new diagnostic modalities of EUS for pancreatobiliary diseases Contrast-enhanced harmonic endoscopic ultrasonography for pancreatobiliary diseases Masayuki Kitano, 1 Ken Kamata, 1 Hajime Imai, 1 Takeshi Miyata, 1 Satoru Yasukawa, 2 Akio Yanagisawa 2 and Masatoshi Kudo 1 1 Department of Gastroenterology and Hepatology, Kinki University Faculty of Medicine, Osaka and 2 Department of Surgical Pathology, Kyoto Prefectural University of Medicine, Kyoto, Japan The combination of second-generation ultrasound contrast agents and an endoscopic ultrasonography (EUS) system with a broad-band transducer has allowed contrast-enhanced harmonic imaging in the field of EUS. In contrast-enhanced harmonic EUS (CH-EUS), diffuse homogeneous enhancement is obtained in normal parenchyma of the pancreas. The bile duct and pancreatic duct are depicted as non-enhanced ductal structures with strong contrast in comparison to the surrounding parenchyma. CH-EUS identifies pancreatic adenocarcinomas as solid lesions exhibiting hypo-enhancement with a sensitivity and specificity of 88 96% and 88 94%, respectively. In particular, % of falsenegative cases in endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) are correctly classified by CH-EUS, suggesting CH-EUS complements EUS-FNA. Moreover, CH-EUS improves depiction of some subtle lesions in conventional EUS, thus facilitating EUS-FNA. For quantitative perfusion analysis, a time intensity curve (TIC) for the region of interest can be generated during CH-EUS. The maximum intensity gain and the echo intensity reduction rate from the peak at 1 min obtained by TIC can be used for differentiation of pancreatic adenocarcinoma from other tumors. CH-EUS is also useful for differentiation of invasive intraductal papillary mucinous neoplasms (IPMN) from non-invasive IPMN, identification of malignant lesions in the gallbladder, and T- and N-staging of pancreatobiliary tumors. Key words: contrast-enhanced harmonic endoscopic ultrasonography (CH-EUS), endoscopic ultrasonography (EUS), pancreatic carcinoma, pancreatobiliary disease INTRODUCTION CONTRAST-ENHANCED HARMONIC IMAGING was developed to enhance ultrasound images by intravenously infusing ultrasound contrast agents composed of microbubbles of approximately 2 5 μm in diameter. 1 4 The main principle of contrast-enhanced harmonic imaging is to selectively depict signals from the microbubbles of the ultrasound contrast agents by filtering signals from the tissue (Fig. 1). 1 4 When exposed to ultrasonic beams with a certain range of acoustic power, microbubbles are disrupted or resonated, and this releases a large amount of harmonic signals (Fig. 1). When tissues and microbubbles receive transmitted ultrasound waves, the harmonic content from the microbubbles is higher than that from the tissues (Fig. 1). Selective Corresponding: Masayuki Kitano, Department of Gastroenterology and Hepatology, Kinki University Faculty of Medicine, Ohno-higashi, Osaka-sayama , Japan. Received 15 December 2014; accepted 27 January depiction of the second harmonic component visualizes signals from microbubbles more strongly than those from tissues. 1 4 Levovist (Bayer Schering Pharma, Berlin, Germany), the first generation of ultrasound contrast agents composed of air with a palmitic acid shell, requires high acoustic power to release harmonic signals by resonation, which the microarray probe for endoscopic ultrasound (EUS) does not produce. 1 3 By contrast, the second generation of ultrasound contrast agents including Sonazoid (Daiichi-Sankyo, Tokyo, Japan; GE Healthcare Milwaukee, WI, USA), SonoVue (Bracco SpA, Milan, Italy) and Definity (Lantheus Medical Imaging, Billerica, MA, USA), which are composed of other gases (perfluorobutane, sulfur hexafluoride and perflutren, respectively) with a phospholipid or lipid shell, are more suitable for a small transducer equipped with an echoendoscope because they resonate with a lower acoustic power than Levovist. 3,4 The combination of second-generation ultrasound contrast agents and an EUS system with a broadband transducer has allowed contrast-enhanced harmonic imaging in the field of EUS. 3,5 bs_bs_banner 60

2 Digestive Endoscopy 2015; 27 (Suppl. 1): CH-EUS for pancreatobiliary diseases 61 Figure 1 Principle of contrast enhanced harmonic imaging. When exposed to ultrasonic beams with a certain range of acoustic power, microbubbles are disrupted or resonated, and this releases a large amount of harmonic signals. When tissues and microbubbles receive transmitted ultrasound waves, the harmonic content from the microbubbles is higher than that from the tissues. Selective depiction of the second harmonic component visualizes signals from microbubbles more strongly than those from tissues. BASIC TECHNIQUE OF CONTRAST-ENHANCED HARMONIC EUS WHEN A LESION is depicted in the digestive tract or pancreatobiliary system, contrast-enhanced harmonic EUS (CH-EUS) helps to characterize it by image enhancement. 5 Before carrying out CH-EUS, the ideal imaging plane of each lesion for CH-EUS is determined during conventional EUS and the presetting is subsequently conditioned. The monitor is changed to dual imaging with the specific mode for CH-EUS (CH-EUS mode) and fundamental B mode (monitor mode). Before infusion of the ultrasound contrast agent, the image on the specific mode for CH-EUS is dark. 5 The MI, a unitless number that reflects the acoustic power based on the derated peak rarefactional pressure (p) and the fundamental frequency (f) (MI = p/f 1/2 ), is set to Immediately before carrying out contrast enhancement, the ultrasound contrast agents are reconstituted with sterile water. A bolus injection of the ultrasound contrast agent is given through a 22-gauge cannula placed in the antecubital vein. 5 This is followed by a 10-mL saline solution flush to ensure that the entire contrast agent was given into the circulation system. In CH-EUS mode, signals from microbubbles appear approximately 10 s after infusion and peak s after infusion (Fig. 2). 5 When signals peak, diffuse homogeneous enhancement is obtained in normal parenchyma of the pancreas (Fig. 2). 5 The bile duct and pancreatic duct are depicted as non-enhanced ductal structures with strong contrast in comparison to the surrounding parenchyma (Fig. 2). Real-time observation can be continued for longer than 1 min. ENHANCEMENT PATTERNS OF PANCREATIC SOLID LESIONS WITH CH-EUS FOR PANCREATIC DISEASES, the main purpose of CH-EUS is to characterize a solid lesion detected by conventional EUS. The characterization of solid lesions, particularly the differentiation of inflammatory tumors from neoplasms, is crucial in order to make decisions regarding treatment. However, it is sometimes difficult to characterize solid lesions with conventional EUS alone. 6,7 CH-EUS helps this characterization by analyzing the relative intensity of enhancement compared with the surrounding tissue In CH-EUS, solid lesions in the pancreas are categorized into three to four patterns according to the intensity of enhancement: non-enhancement; hypo-enhancement (Fig. 3a); isoenhancement (Fig. 3b); and hyper-enhancement (Fig. 3c) Interobserver agreement among endosonographers for CH-EUS was satisfactory (κ coefficient = ). 8,9,12 Non-experienced endosonographers demonstrated comparable interobserver agreement with experienced ones, suggesting that CH-EUS is an extremely reproducible tool with a short learning curve. 9,12 DIAGNOSIS OF PANCREATIC ADENOCARCINOMAS ACCORDING TO THE ENHANCEMENT PATTERNS OF CH-EUS MOST PANCREATIC CARCINOMAS exhibit hypoenhancement in CH-EUS (Fig. 3a) A recent metaanalysis of reports concerning contrast-enhanced EUS showed that this method identifies pancreatic adenocarcinomas as solid lesions exhibiting hypo-enhancement with a

3 62 M. Kitano et al. Digestive Endoscopy 2015; 27 (Suppl. 1): a b Fusaroli et al. reported that identification of hypoenhancing masses with an inhomogeneous pattern in CH-EUS is a sensitive and accurate identifier of patients with adenocarcinoma (sensitivity and accuracy of 96% and 82%, respectively). 7 This identification by CH-EUS is more accurate than the finding of a hypoechoic lesion using standard EUS (sensitivity and accuracy of 85% and 58%, respectively). 7 We previously compared CH-EUS and contrast-enhanced multidetector-row computed tomography (MDCT) for the identification of adenocarcinomas. 8 CH-EUS (sensitivity and specificity of 91.2% and 94.4%, respectively) was superior to MDCT (sensitivity and specificity of 70.6% and 91.6%, respectively) in diagnosing small ( 2 cm) carcinomas (P < 0.05). 8 c Figure 2 Time course of contrast-enhanced harmonic endoscopic ultrasonography (CH-EUS) images in a pancreas without any findings suggestive of lesions (pancreas head). (a) CH-EUS image before infusion of the contrast agent. No signals from microbubbles can be observed. (b) CH-EUS image 13 s after infusion of the contrast agent. Spotty signals from microbubbles (arrows) and fine branching vessels (arrowheads) appear in the pancreas. (c) CH-EUS image 21 s after infusion of the contrast agent. Diffuse parenchymal perfusion of microbubbles can be imaged. The main pancreatic duct is depicted as an avascular structure with strong contrast to the surrounding tissue (arrow). pooled sensitivity and specificity of 94% and 89%, respectively. 10 However, this meta-analysis not only included CH-EUS but also contrast-enhanced Doppler EUS which suffers from artifacts such as blooming. 5,11 CH-EUS FOR EUS-FNA THREE STUDIES COMPARED CH-EUS with EUSguided fine-needle aspiration (EUS-FNA) in the identification of adenocarcinomas. 8,9,11 In these, the sensitivity and specificity of hypo-enhancement in CH-EUS for diagnosing pancreatic adenocarcinoma were 89 96% and 88 94%, respectively, which were not significantly different from the corresponding values in EUS-FNA of 72 95% and 100%, respectively. 8,9,11 However, % of false-negative cases in EUS-FNA were correctly classified by CH-EUS. 8,9,11 These results suggest that CH-EUS could help to decide between surgery and follow up when the results of EUS- FNA are inconclusive. CH-EUS is also useful for identification of the target of EUS-FNA. 7,8,13 CH-EUS improves depiction of some subtle lesions in conventional EUS, thus facilitating EUS-FNA (Fig. 4). 7,8,13 Moreover, CH-EUS plays an important role in finding a specific site within a lesion that would be more suitable for EUS-FNA than other sites. 14 Identification of the avascular sites in a lesion may help avoid sampling necrotic areas and improve the sensitivity of EUS-FNA in the diagnosis of pancreatic tumors. 14 QUANTITATIVE PERFUSION ANALYSIS WITH TIME INTENSITY CURVE DURING CH-EUS FOR QUANTITATIVE PERFUSION analysis, a time intensity curve (TIC) for region of interest (ROI) can be generated during CH-EUS. Many variables are reported for a TIC, including the ratio of uptake inside the mass to uptake in the surrounding parenchyma, median intensity, maximum intensity, time to peak, area under the curve, and echo intensity reduction rate Imazu et al. reported that maximum intensity gain was the best variable to differentiate

4 Digestive Endoscopy 2015; 27 (Suppl. 1): CH-EUS for pancreatobiliary diseases 63 a b c Figure 3 Typical images of pancreatic solid tumors on contrast-enhanced harmonic endoscopic ultrasonography (EUS). (Left) Conventional EUS image. (Right) Contrast-enhanced harmonic EUS image. (a) Ductal carcinoma with hypo-enhancement. Conventional EUS (left) shows a hypoechoic area (arrowheads) of 23 mm in diameter at the pancreas tail. CH-EUS (right) indicates that the area has hypo-enhancement (arrowheads) compared with the surrounding tissue. (b) Tumor-forming chronic pancreatitis with iso-enhancement. Conventional EUS (left) shows a hypoechoic area (arrowheads) of 22 mm in diameter at the pancreas head. CH-EUS (right) indicates that the area has homogeneous enhancement similar to the surrounding tissue. The margin is not observed on CH-EUS. (c) Neuroendocrine tumor with hyper-enhancement. Conventional EUS (left) shows a hypoechoic area (arrowheads) of 14 mm in diameter at the pancreas tail. CH-EUS (right) indicates that the area has hyper-enhancement (arrowheads) compared with the surrounding tissue.

5 64 M. Kitano et al. Digestive Endoscopy 2015; 27 (Suppl. 1): a b Figure 4 Contrast-enhanced harmonic endoscopic ultrasonographyguided fine-needle aspiration (CH-EUS- FNA for a subtle lesion in the pancreas. (a) Conventional EUS (left) shows a subtle hypoechoic lesion at the pancreas body. CH-EUS (right) shows clear demarcation between the lesion and the surrounding tissue (arrowheads). (b) On real-time imaging with CH-EUS, the lesion with hypo-enhancement (arrowheads) is punctured with an EUS- FNA needle (arrow). (c) Histological examination of samples obtained by CH-EUS-FNA shows relative noncohesive, pleomorphic mononuclear cells admixed with multinucleated giant cells (arrow). The final diagnosis of the lesion is anaplastic carcinoma. c

6 Digestive Endoscopy 2015; 27 (Suppl. 1): CH-EUS for pancreatobiliary diseases 65 autoimmune pancreatitis from pancreatic carcinoma with a sensitivity of 100% and a specificity of 100%. 15 On the other hand, Matsubara et al. reported that the echo intensity reduction rate from the peak at 1 min was greatest in pancreatic adenocarcinomas. 16 They concluded that when TICs were generated during CH-EUS, sensitivity, specificity, and accuracy increased to 95.8%, 92.6%, and 94.7%, respectively. 16 Although the most reliable variable of TICs should be identified by further large multicenter studies, this quantitative perfusion analysis may be complementary to classification according to enhancement patterns to characterize pancreatic solid lesions. DIFFERENTIATION OF MALIGNANT AND BENIGN INTRADUCTAL PAPILLARY MUCINOUS NEOPLASMS WITH CONTRAST-ENHANCED EUS EUS IS THE most sensitive method for detection of the mural nodule in intraductal papillary mucinous neoplasms (IPMNs). Ohno et al. assessed whether enhancement patterns of contrast-enhanced EUS using color Doppler mode differentiate malignant and benign IPMNs. 19 In their report, mural nodules were classified into 4 types according to the enhancement patters: low papillary nodule, polypoid nodule, papillary nodule and invasive nodule. 19 When the presence of papillary module or invasive nodule was diagnosed as evident of invasive IPMN, the sensitivity, specificity and accuracy were 84.2%, 79.4%, and 80.5%, respectively. 19 Multivariable logistic regression analysis showed that contrast (OR, 10.8) and symptomatic IPMNs (OR, 4.31) were significant for malignancy. 19 They concluded that the type of mural nodules obtained by CE-EUS may be the most reliable diagnostic method to differentiate malignant from benign IPMNs. CH-EUS more clearly depicts morphological structures of mural nodules without blooming artifacts than contrast-enhanced Doppler EUS (Fig. 5), and may be also useful for identification of invasive IPMNs. CHARACTERIZATION OF GALLBLADDER LESIONS WITH CH-EUS THREE ARTICLES REPORTED that characterization of gallbladder diseases with CH-EUS Imazu et al. compared conventional EUS and CH-EUS for the differential diagnosis of gallbladder wall thickening. 20 In their report, the inhomogeneous enhanced pattern in CH-EUS was a strong predictive factor of malignant gallbladder wall thickening, and the overall accuracy for diagnosing malignant gallbladder wall thickening was significantly higher for Figure 5 Contrast-enhanced harmonic endoscopic ultrasonography (CH-EUS) image of an intraductal papillary mucinous neoplasm. Slight dilatation of the main pancreatic duct (MPD; 4 mm) is observed at the pancreas head. There is a mural nodule with contrast enhancement in the dilated duct (arrowheads). CH-EUS (94.4%) than for conventional EUS (73.1%). 20 Choi et al. assessed the utility of CH-EUS for differential diagnosis between benign and malignant polyps of the gallbladder. 21 An irregular vessel pattern determined by CH-EUS aided the diagnosis of malignant polyps with a sensitivity and specificity of 90.3% and 96.6%, respectively. 21 The presence of perfusion defects, as determined by CH-EUS, was used to diagnose malignant polyps with a sensitivity and specificity of 90.3% and 94.9%, respectively. 21 In eight cases, management changed after carrying out contrast-enhanced EUS, suggesting that CH-EUS slightly improves diagnostic accuracy in comparison to conventional EUS. STAGING OF PANCREATOBILIARY TUMORS WITH CH-EUS FOR T-STAGING, IMAZU et al. compared conventional tissue harmonic EUS and CH-EUS, and showed the accuracy of CH-EUS (92.4%) was significantly higher than that for conventional tissue harmonic EUS (69.2%) (P < 0.05). 23 In particular, CH-EUS was superior to conventional tissue harmonic EUS in terms of specificity for identification of portal venous involvement. 23 For N-staging, Kanamori et al. compared features of benign and malignant lymph nodes with contrast-enhanced Doppler EUS, and found a defect of enhancement that diagnosed malignant lymph nodes with a sensitivity of 100% and a specificity of 82%. 24 The diagnostic ability of contrast-enhanced Doppler EUS was superior to the morphological classification based

7 66 M. Kitano et al. Digestive Endoscopy 2015; 27 (Suppl. 1): a Figure 6 Typical images of lymph nodes with contrast-enhanced harmonic endoscopic ultrasonography (EUS). (Left) Conventional EUS image. (Right) Contrast-enhanced harmonic EUS image. (a) Benign lymph node with homogeneous enhancement. Conventional EUS (left) shows a lymph node of 15 mm in diameter (arrowheads). Contrast-enhanced harmonic EUS (right) indicates that the lymph node has homogeneous enhancement (arrowheads). BD, bile duct; PV, portal vein. (b) Malignant lymph node with heterogeneous enhancement. Conventional EUS (left) shows a lymph node of 21 mm in diameter (arrowheads). Contrast-enhanced harmonic EUS (right) indicates that the lymph node has heterogeneous enhancement (arrowheads). b on conventional EUS (sensitivity and specificity of 88% and 77%, respectively). 24 We previously assessed the CH-EUS images of intra-abdominal lesions of undetermined origin, and classified these lesions into two types according to enhancement patterns: homogeneous (Fig. 6a) and heterogeneous enhancement (Fig. 6b). 25 The sensitivity and specificity with which CH-EUS differentiated malignant from benign lesions were 96.3% and 100%, respectively, suggesting that CH-EUS is useful for N-staging of pancreatobiliary tumors. 25 CONCLUSION DEVELOPMENT OF CH-EUS technique allowed visualization of real-time perfusion imaging of the pancreatobiliary system. CH-EUS improved ability of EUS in detection, characterization and staging of pancreatobiliary tumors. CH-EUS also complements EUS-FNA. However, most studies were carried out in a small number of patients by a single center. Further multicenter studies with larger numbers of patients would prove its utility. CONFLICT OF INTERESTS AUTHORS DECLARE NO conflict of interests for this article. REFERENCES 1 Kudo M. Various contrast-enhanced imaging modes after administration of Levovist. In: Kudo M (ed.). Contrast Harmonic Imaging in the Diagnosis and Treatment of Hepatic Tumors. Tokyo: Springer, 2003; Kitano M, Kudo M, Maekawa K et al. Dynamic imaging of pancreatic diseases by contrast enhanced coded phase inversion harmonic ultrasonography. Gut 2004; 53:

8 Digestive Endoscopy 2015; 27 (Suppl. 1): CH-EUS for pancreatobiliary diseases 67 3 Kitano M, Kudo M, Sakamoto H et al. Preliminary study of contrast-enhanced harmonic endosonography with secondgeneration contrast agents. J. Med. Ultrason. 2008; 35: Quaia E. Classification and safety of microbubble-based contrast agents. In: Quaia E (ed.). Contrast Media in Ultrasonography. Basic Principles and Clinical Applications. Berlin: Springer, 2005; Kitano M, Sakamoto H, Matsui U et al. A novel perfusion imaging technique of the pancreas: Contrast-enhanced harmonic EUS (with video). Gastrointest. Endosc. 2008; 67: Kitano M, Kudo M, Sakamoto H et al. Endoscopic ultrasonography and contrast-enhanced endoscopic ultrasonography. Pancreatology 2011; 11 (Suppl 2): Fusaroli P, Spada A, Mancino MG et al. Contrast harmonic echo-endoscopic ultrasound improves accuracy in diagnosis of solid pancreatic masses. Clin. Gastroenterol. Hepatol. 2010; 8: Kitano M, Kudo M, Yamao K et al. Characterization of small solid tumors in the pancreas: Contrast: The value of contrastenhanced harmonic endoscopic ultrasonography. Am. J. Gastroenterol. 2012; 107: Gincul R, Palazzo M, Pujol B et al. Contrast-harmonic endoscopic ultrasound for the diagnosis of pancreatic adenocarcinoma: A prospective multicenter trial. Endoscopy 2014; 46: Gong TT, Hu DM, Zhu Q. Contrast-enhanced EUS for differential diagnosis of pancreatic mass lesions: A meta-analysis. Gastrointest. Endosc. 2012; 76: Napoleon B, Alvarez-Sanchez MV, Gincoul R et al. Contrastenhanced harmonic endoscopic ultrasound in solid lesions of the pancreas: Results of a pilot study. Endoscopy 2010; 42: Fusaroli P, Kypraios D, Mancino MG et al. Interobserver agreement in contrast harmonic endoscopic ultrasound. J. Gastroenterol. Hepatol. 2012; 27: Romagnuolo J, Hoffman B, Vela S et al. Accuracy of contrast enhanced harmonic EUS with a second-generation perflutren lipid microsphere contrast agent (with video). Gastrointest. Endosc. 2011; 73: Kitano M, Sakamoto H, Komaki T et al. FNA guided by contrast-enhanced harmonic EUS in pancreatic tumors. Gastrointest. Endosc. 2009; 69: A328 A Imazu H, Kanazawa K, Mori N et al. Novel quantitative perfusion analysis with contrast-enhanced harmonic EUS for differentiation of autoimmune pancreatitis from pancreatic carcinoma. Scand. J. Gastroenterol. 2012; 47: Matsubara H, Itoh A, Kawashima H et al. Dynamic quantitative evaluation of contrast enhanced endoscopic ultrasonography in the diagnosis of pancreatic diseases. Pancreas 2011; 40: Gheonea DI, Streba CT, Ciurea T, Saftoiu A. Quantitative low mechanical index contrast enhanced endoscopic ultrasound for the differential diagnosis of chronic pseudotumoral pancreatitis and pancreatic cancer. BMC Gastroenterol. 2013; 13: Seicean A, Badea R, Stan-Iuga R, Mocan T, Gulei I, Pascu O. Quantitative contrast-enhanced harmonic endoscopic ultrasonography for the discrimination of solid pancreatic masses. Ultraschall Med. 2010; 31: Ohno E, Hirooka Y, Itoh A et al. Intraductal papillary mucinous neoplasms of the pancreas: Differentiation of malignant and benign tumors by endoscopic ultrasound findings of mural nodules. Ann. Surg. 2009; 249: Imazu H, Mori N, Kanazawa K et al. Contrast-enhanced harmonic endoscopic ultrasonography in the differential diagnosis of gallbladder wall thickening. Dig. Dis. Sci. 2014; 59: Choi JH, Seo DW, Choi JH et al. Utility of contrast-enhanced harmonic EUS in the diagnosis of malignant gallbladder polyps (with videos). Gastrointest. Endosc. 2013; 78: Park CH, Chung MJ, Oh TG et al. Differential diagnosis between gallbladder adenomas and cholesterol polyps on contrast-enhanced harmonic endoscopic ultrasonography. Surg. Endosc. 2013; 27: Imazu H, Uchiyama Y, Matsunaga K et al. Contrast-enhanced harmonic EUS with novel ultrasonographic contrast (Sonazoid) in the preoperative T-staging for pancreaticobiliary malignancies. Scand. J. Gastroenterol. 2010; 45: Kanamori A, Hirooka Y, Itoh A et al. Usefulness of contrast enhanced endoscopic ultrasonography in the differentiation between malignant and benign lymphadenopathy. Am. J. Gastroenterol. 2006; 101: Xia Y, Kitano M, Kudo M et al. Characterization of intraabdominal lesions of undetermined origin by contrast-enhanced harmonic EUS (with video). Gastrointest. Endosc. 2010; 72: